Recent advances in elucidating the genetic basis of systemic sclerosis

Abstract

Purpose of reviewSystemic sclerosis (SSc) is a complex autoimmune disorder that affects the connective tissue and causes severe vascular damage and fibrosis of the skin and internal organs. There are recent advances in the field that apply novel methods to high throughput genotype information of thousands of patients with SSc and provide promising results towards the use of genomic data to help SSc diagnosis and clinical care.Recent findingsThis review addresses the development of the first SSc genomic risk score, which can contribute to differentiating SSc patients from healthy controls and other immune-mediated diseases. Moreover, we explore the implementation of data mining strategies on the results of genome-wide association studies to highlight subtype-specific HLA class II associations and a strong association of the HLA class I locus with SSc for the first time. Finally, the combination of genomic data with transcriptomics informed drug repurposing and genetic association studies in well characterized SSc patient cohorts identified markers of severe complications of the disease.SummaryEarly diagnosis and clinical management of SSc and SSc-related complications are still challenging for rheumatologists. The development of predictive models and tools using genotype data may help to finally deliver personalized clinical care and treatment for patients with SSc in the near future.

Potential angiogenic, immunomodulatory, and antifibrotic effects of mesenchymal stem cell-derived extracellular vesicles in systemic sclerosis

“…In addition, genetic factor studies at different levels of genetic information have advanced considerably with the development of technology and lower costs. There is a close relationship between human leukocyte antigen (HLA) locus genes and SSc, and 32 non-HLA loci have been identified (4). This opens up promising possibilities for the use of precision medicine for SSc patients.…”

Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis

“…Genetic modifications are known to play a significant role in SSc pathogenesis, but taken alone they do not allow clarification of the occurrence of the disease [ 59 , 60 ]. Indeed, SSc is thought to be determined by complex interactions between genetic predispositions and epigenetic modifications such as DNA methylation, histone modifications, and microRNAs (miRNAs), which are able to regulate gene expression without altering the DNA sequence [ 61 , 62 , 63 ].…”

“…Indeed, SSc is thought to be determined by complex interactions between genetic predispositions and epigenetic modifications such as DNA methylation, histone modifications, and microRNAs (miRNAs), which are able to regulate gene expression without altering the DNA sequence [ 61 , 62 , 63 ]. In the last two decades, besides the known contribution of human leukocyte antigen (HLA) class II haplotypes to the risk of developing SSc, various multicenter studies discovered several non-HLA loci contributing to SSc pathogenesis, but very few pointed toward potential genetic modifications relevant for disease vasculopathy [ 59 , 60 ]. In 2020, Takagi et al genotyped four single nucleotide polymorphisms of the HIF1A gene in a Japanese SSc population and found that the AA genotype at rs12434438 was not only significantly increased in SSc patients with PAH compared to those without but also associated with the severity of this pulmonary condition [ 64 ].…”

Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets

“…In addition, the disease represents a real social burden owing to its heavy impact on facial appearance, orofacial functions, and everyday life activities [ 3 ]. Although the etiology of SSc remains unknown, a large body of evidence now indicates that genetic susceptibility factors have an essential role in the onset and the evolution of this disease [ 4 ]. In recent years, there have been substantial advances in the understanding of SSc pathogenesis, as well as in early diagnosis and clinical management of patients.…”